Although Interferon-1 (IFN-?) is a cytokine known for its antiviral effects, it may be also be important for normal functioning of the adaptive and innate immune system at low, physiologic concentrations, while it is immunosuppressive at high concentrations. In this respect, elevated levels of IFN-?? are not correlated with control of HIV-1 infection and are likely a sign of immune activation that contributes to HIV-1 pathogenesis. Our preliminary data show that HIV-1-induced IFN-?? production inhibits early stages of human T cell development by impairing the IL-7/IL7R pathway. In addition we found that in normal thymus tissue, mature thymocytes and plasmacytoid dendritic cells (pDC) constitutively express IFN-?? and its secondary response protein MxA at low levels. In contrast, lymphocytes and pDC in peripheral lymphoid organs (from the same donor) do not constitutively express IFN-??. These results support the notion that in the thymus, low levels of IFN-?? are important for normal functioning of T cell development. However, high levels of IFN-?? and prolonged HIV-1-induced IFN-?? are likely to disturb normal T cell development and thereby peripheral T cell reconstitution. Thus, although IFN-?? can suppress HIV-1 replication in vitro, and IFN-?? therapy has shown mixed results in vivo, it is likely that its immunosuppressive effects outweigh its antiviral activity thereby contributing to HIV-1 pathogenesis. Based on our preliminary data our central hypothesis is that high levels of IFN-?? which accompany immune, activation during HIV-1 infection, impair T cell (re)generation and that pDC play an essential role in this process. We will use our established methods as well as novel approaches and unique reagents to test our hypothesis. Experiments will be performed with HIV-induced IFN-?? in humanized mouse models and in vitro T cell development assays as proposed in the following specific aims: 1. To investigate the mechanisms by which HIV-1 induced IFN-?? inhibits T-cell development and reconstitution. 2. To characterize the role of plasmacytoid dendritic cells (pDC) in the thymus. 3. To investigate the mechanisms by which IFN-?? induced MxA or other secondary response proteins suppress replication of CCR5- and CXCR4-tropic HIV-1. The present proposal represents a unique collaborative approach to elucidate the role of IFN-?? and pDC in T cell development and reconstitution in HIV-1 infection. Information gained from the proposed experiments will have implications for the treatment of HIV-1 infected patients with immunomodulatory therapies. PUBLIC HEALTH RELEVANCE: Although Interferon-?? (IFN-??) is a cytokine known for its antiviral effects, it may also be important for normal functioning of the adaptive and innate immune system at low, physiologic, concentrations while it is immunosuppressive at high concentrations. In this respect, elevated levels of IFN-?? are not correlated with control of HIV-1 infection and are likely a sign of immune activation that contributes to HIV-1 pathogenesis. The present proposal represents a unique collaborative approach to elucidate the role of IFN-?? and pDC in T cell development and reconstitution in HIV-1 infection. Insight into the molecular mechanisms underlying the IFN-?? induced block of T cell development will enhance the development of immunomodulatory therapeutic interventions to counteract impaired T cell development and regeneration.